Premature ejaculation (PE) is the most prevalent form of male sexual dysfunction, affecting as many as 30% of American men. The diagnostic criteria for premature ejaculation (PE) as provided by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV, 1994) are: A. Persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it. The clinician must take into account factors that affect duration of the excitement phase, such as age, novelty of the sexual partner or situation, and recent frequency of sexual activity. B. The disturbance causes marked distress or interpersonal difficulty. C. The PE is not due exclusively to the direct physiological effects of a substance (e.g. a drug or medication) or a general medical condition. American Psychiatric Association, Diagnostic and statistical manual of mental disorders, fourth edition. Washington, D.C.: American Psychiatric Association (1994).
The condition that ejaculation occurs “before the person desires it” implies a lack of voluntary control. In some definitions of PE, the lack of voluntary control is primary, irrespective of time after penetration, number of thrusts or orgasm by the partner. As a practical matter, PE is often operationally defined as the latency to ejaculation after vaginal penetration, although there is a lack of agreement as to the defining minimum latency, ranging from 1 minute to 7 minutes. As an empirical matter, it has been reported in a study of 110 men suffering from lifelong PE that 90% had a intravaginal ejaculation latency time (IELT) less than 1 minute when measured by stopwatch. See, generally, Waldinger, M. D., The neurobiological approach to premature ejaculation, J. Urol., 2002, 168: 2359-2367.
Recent neurophysiological studies have suggested that the ejaculatory reflex consists of two reflexes: the glans-vagal reflex that brings semen to the posterior urethra, and the urethromuscular reflex that ejects the semen to the exterior (Shafik, A., The mechanism of ejaculation: the glans-vasal and urethromuscular reflexes. Arch Androl. 1998 41(2):71-8). The first reflex is initiated by stimulation of the genital receptors, and it travels through the pudendal nerves to the sacral cord with a final destination at the limbic lobe and the hypothalamus. The second reflex is transmitted from the urethra to the ejaculatory center (segments S2-4). Efferent fibers of pudendal parasympathetic nerves send signals to the ganglia; these signals result in the release of neurotransmitters which, by depolarizing perineal muscles, translate into rhythmic contractions and seminal emission. A dysfunction of either or both of these reflexes could result in ejaculatory disorders.
One hypothesis of PE proposes that there is a threshold or set point level of sexual arousal at which ejaculation occurs. Under this hypothesis, men with a lower threshold would be predicted to have shorter IELT. However, such a hypothesis does not specify whether the threshold is set centrally, by synaptic interactions in the central nervous system, or by peripherally, the threshold of the afferent sensory input. Both alternatives have been therapeutic targets.
Topical anesthetics have been applied to the penis to block conduction in somatosensory afferent neurons. For example, an open pilot, unblinded study was done using lidocaine-prilocalne cream in 11 healthy, married men with premature ejaculation without organic or erectile problems. The patients were instructed to apply 2.5 gm of the cream 30 minutes before sexual contact and to cover the penis with a condom. Nine of the eleven patients reported an improvement (Berkovitch, et al. Efficacy of prilocalne-lidocaine cream in the treatment of premature ejaculation. J. Urol. 1995 154(4):1360-1).
Several pharmacological approaches have been directed at a putative threshold setting mechanism in the central nervous system at spinal or supraspinal levels. Many are serotonergic reuptake inhibitors. A non-selective serotonergic reuptake inhibitor, the tricyclic antidepressant chlomipramine, has been used to treat PE. Several selective serotonergic reuptake inhibitors (SSRIs) have been used to treat PE, including fluoxetine, paroxetine and sertaline. However, the serotonergic reuptake inhibitors generally have undesirable side-effects. See McCullough, A. R. & Melman, “Ejaculatory Disorders,” pp. 351-370 in Mulcahy, J. J., ed., Male Sexual Function: A Guide to Clinical Management, Humana Press, Totowa, N.J., 2001.
PE may be present with erectile dysfunction (ED) in a number of patients, a factor that might affect the choice of treatment, but there is no unanimity on either issue. In one study, eighty-seven patients with PE were categorized into two groups: primary PE and PE in sildenefil-treated ED patients (Chia, S., Management of premature ejaculation—a comparison of treatment outcome in patients with and without erectile dysfunction. Int J. Androl. 2002 25(5):301-5). Both groups of patients were treated with 50 mg sertraline four hours before the expected time of sex. Twenty-eight percent of the sildenefil-treated ED patients developed PE. No significant difference in the pre-treatment mean ejaculation latency for the PE and PE+ED groups was reported (46 vs. 34.6 sec, respectively). However, a highly significant difference in the ejaculation latency between the two groups after treatment with sertraline for 6 months (247.2 vs. 111.6 sec for PE and PE+ED, respectively) was reported. The study concluded that while selective serotonin re-uptake inhibitors (SSRIs) were effective in the management of primary PE, they were not as effective in patients with sildenefil-corrected ED. However, a prospective, double-blind, placebo-controlled, crossover study of the effect of another SSRI, fluoxetine, on sexual function in men with premature ejaculation and/or erectile dysfunction reported that the latency to ejaculation increased significantly in the PE+ED group (p=0.03) and in the PE and the PE+ED group taken together (p=0.007) but not in the PE group alone. See Haensel, S. M., et al. Fluoxetine and premature ejaculation: a double-blind, crossover, placebo-controlled study. J Clin Psychopharmacol. 1998 18(1):72-7. And while the Chia, 2002, study reported that ED patients may develop PE, others have reported that life-long PE patients do not develop ED (Waldinger, 2002, p. 2364).
Prostaglandin E1 (PGE1) is a derivative of prostanoic acid, a 20-carbon atom lipid acid, represented by the formula:

and is commercially available, e.g., from Chinoin Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under the designation “Alprostadil USP,” from Pharmacia & Upjohn under the designation “Caverject”. Prostaglandin E1 complexed with alpha-cyclodextrin is available as alprostatil alfadex from Ono Pharmaceuticals (Japan) and in an injectable form under the designation “Edex®” or “Viradex®” from Schwarz Pharma (Germany).
In one commercially available form (MUSE®, Vivus, Menlo Park Calif.), alprostadil is administered in a pellet deposited in the urethra using an applicator with a hollow stem 3.2 cm in length and 3.5 mm in diameter (Padma-Nathan, H., et al., N. Engl. J. Med., 336: 1-7 (1997), see especially FIG. 1). In the home treatment portion of the Padma-Nathan et al. study, 32.7% of the patients (10.8% of administrations) receiving MUSE® complained of penile pain and 5.1% experienced minor urethral trauma, compared to 3.3% and 1.0%, respectively, of the patients receiving placebo. Frequency of report of these side effects has varied in subsequent studies: MUSE® producing penile pain in 17-23.6% of administrations, compared to 1.7% with placebo and minor urethral bleeding reported by 4.8% of patients (Peterson, C. A., et al., J. Urol., 159: 1523-1528 (1998)). In a study on a European population, 31% MUSE® patients reporting penile pain or burning sensations, 4.8% reporting urethral bleeding, and 2.9% reporting severe testicular pain (Porst, H., Int. J. Impot. Res., 9:187-192 (1997)). The percent of patients responding to MUSE® treatment, defined as having at least one erection considered sufficient for intercourse, has been reported to be 43% (Porst, 1997), 65.9% (Padma-Nathan et al., 1997) and 70.5% (Peterson et al., 1998), although published editorial comment has suggested that the percent of patients responding in the latter two studies is more properly reported as 30-40% (Benson, G., J. Urol., 159: 1527-1528 (1998)).
Intraurethral application of a preparation of 1 mg prostaglandin E1 in phosphatidylcholine liposomes in 1 ml polyoxyethylene glycol has been reported to be less effective than intracavernosal injection of prostaglandin E1 (Englehardt, P. F., et al., British J. Urology, 81: 441-444, 1998). No ED patients receiving the liposomal preparation achieved complete penile rigidity, and only 6 of 25 patients achieved an erection adequate for vaginal penetration. In contrast, intracavernosal injection of prostaglandin E1 produced erections adequate for vaginal penetration or complete rigidity in 23 of 25 of the same ED patients. The authors suggested that the transurethral effect of the prostaglandin E1 probably arises by diffusion of prostaglandin E1 first into the corpus spongiosum and then into the corpus cavernosum.
Recently, intrameatal (also referred to as “meatal”) application of a topical PGE1 composition comprising at least one penetration enhancer has been shown to be a non-invasive alternative to intracavernosal injection or transurethral suppositories for the treatment of erectile dysfunction (see U.S. Pat. No. 6,323,241 and U.S. published patent application 2003/0220292, the contents of which are hereby incorporated in their entirety). Intrameatal application is the application of medication to the tip of the penis into the navicular fossa by holding the penis upright, holding the meatus open and dropping the medication into the navicular fossa, without introducing the medication container into the meatus.